S-Methylcysteine (SMC) Ameliorates Intestinal, Hepatic, and Splenic Damage Induced by Cryptosporidium parvum Infection Via Targeting Inflammatory Modulators and Oxidative Stress in Swiss Albino Mice

Cryptosporidiosis has been proposed to be one of the major causes of diarrhoeal disease in humans worldwide that possesses zoonotic concern. Thereby, this study investigated the potential effects of s-Methylcysteine (SMC) on the parasite in vivo followed by the measurement of cytokines, oxidative stress parameters, and an investigation of the major histopathological changes. Sixty male Swiss albino mice weighing 20–25 g were allocated equally into five groups and orally administered saline only (control), SMC only (SMC50) (50 mg/kg b.w.), and 104Cryptosporidium parvum oocysts per mouse via an esophageal tube (C + ve untreated). The fourth and fifth groups (C + SMC25, C + SMC50) administrated 104C. parvum oocysts combined with SMC25 (low dose) and 50 (high dose) mg/kg b.w., respectively. At days 7 and 14 post-infection (PI), the feces was collected from each group in order to count C. parvum oocysts. After two weeks of treatment, the animals were euthanized and the serum was collected for biochemical analysis. Next, the intestinal, spleen, and liver sections were dissected for histopathological examination. The results revealed lower oocyst numbers in the C + SMC25 and C + SMC50 groups compared to the infected untreated group. Moreover, higher doses of SMC treatment significantly reduced the enteritis induced by C. parvum in a dose-dependent manner. The hepatic lesions were also mitigated as demonstrated in C + SMC25 and C + SMC50 groups unlike the infected group via lowering the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes and increasing albumin and globulin serum levels. SMC administration also reduced cytokines production (SAP, TNF-α, IL-6, and IFN-γ) mediated by Cryptosporidium infection in contrast to the infected untreated group. There were marked lymphoid depletion and amyloidosis observed in the infected untreated group, while the treated groups showed obvious increase in the lymphoid elements. Moreover, the scoring of intestinal parasites, hepatic, and splenic lesions in the SMC-treated groups exhibited significantly lower pathological lesions in different organs in a dose-dependent manner, compared to the infected untreated group. Our results also revealed a significant change in the malondialdehyde content with an elevation of glutathione and superoxide dismutase in the intestines collected from C + SMC25 and C + SMC50 mice relative to the untreated group. Taken together, our results indicated that SMC could be a promising effective compound for treating and declining C. parvum infestation via restoring structural alterations in different tissues, enhancing antioxidant enzymes, and suppressing the cytokines liberation.

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Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽

10.3390/pharmaceutics13030386 ◽

2021 ◽

Vol 13 (3) ◽

pp. 386

Author(s):

Tung-Hu Tsai ◽

Yu-Jen Chen ◽

Li-Ying Wang ◽

Chen-Hsi Hsieh

Keyword(s):

Stereotactic Body Radiation Therapy ◽

In Vivo Studies ◽

Control Group ◽

High Dose ◽

Dependent Manner ◽

Hep G2 ◽

Time Curve ◽

Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

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Damaging Effects of Bisphenol A on the Kidney and the Protection by Melatonin: Emerging Evidences from In Vivo and In Vitro Studies

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/3082438 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 17

Author(s):

Anongporn Kobroob ◽

Wachirasek Peerapanyasut ◽

Nipon Chattipakorn ◽

Orawan Wongmekiat

Keyword(s):

Oxidative Stress ◽

Bisphenol A ◽

Mitochondrial Function ◽

Dependent Manner ◽

Redox Equilibrium ◽

Membrane Potential Change ◽

Kidney Mitochondria ◽

Dose Dependent

This study investigates the effects of bisphenol A (BPA) contamination on the kidney and the possible protection by melatonin in experimental rats and isolated mitochondrial models. Rats exposed to BPA (50, 100, and 150 mg/kg, i.p.) for 5 weeks demonstrated renal damages as evident by increased serum urea and creatinine and decreased creatinine clearance, together with the presence of proteinuria and glomerular injuries in a dose-dependent manner. These changes were associated with increased lipid peroxidation and decreased antioxidant glutathione and superoxide dismutase. Mitochondrial dysfunction was also evident as indicated by increased reactive oxygen species production, decreased membrane potential change, and mitochondrial swelling. Coadministration of melatonin resulted in the reversal of all the changes caused by BPA. Studies using isolated mitochondria showed that BPA incubation produced dose-dependent impairment in mitochondrial function. Preincubation with melatonin was able to sustain mitochondrial function and architecture and decreases oxidative stress upon exposure to BPA. The findings indicated that BPA is capable of acting directly on the kidney mitochondria, causing mitochondrial oxidative stress, dysfunction, and subsequently, leading to whole organ damage. Emerging evidence further suggests the protective benefits of melatonin against BPA nephrotoxicity, which may be mediated, in part, by its ability to diminish oxidative stress and maintain redox equilibrium within the mitochondria.

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Amaranth Leaf Extract Protects Against Hydrogen Peroxide Induced Oxidative Stress in Drosophila Melanogaster

10.21203/rs.3.rs-322299/v1 ◽

2021 ◽

Author(s):

Johnmark Ndinawe ◽

Hellen W. Kinyi

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Antioxidant Activity ◽

Ascorbic Acid ◽

Drosophila Melanogaster ◽

Leaf Extract ◽

Dependent Manner ◽

Polyphenol Compounds ◽

Dose Dependent

Abstract ObjectiveAmaranths leaves are rich in ascorbic acid and polyphenol compounds which have antioxidant activity. The aim of this study was to evaluate their in vivo antioxidant activity. The effect of consumption of Amaranth leaf extract on in vivo antioxidant activity, catalase enzyme activity and H2O2 induced oxidative stress in Drosophila melanogaster flies was assessed.ResultsConsumption of Amaranth leaf extract was associated with increased survival on exposure to H202 in a dose dependent manner in Drosophila melanogaster flies.

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A possible alternative therapy for type 2 diabetes using Myristica fragrans Houtt in combination with glimepiride: in vivo evaluation and in silico support

Zeitschrift für Naturforschung C ◽

10.1515/znc-2019-0134 ◽

2020 ◽

Vol 75 (3-4) ◽

pp. 103-112

Author(s):

Waheeda Nasreen ◽

Suchitra Sarker ◽

Md. Abu Sufian ◽

F.A. Dain Md. Opo ◽

Mohammad Shahriar ◽

...

Keyword(s):

Blood Glucose ◽

Blood Glucose Level ◽

Binding Affinity ◽

Glucose Level ◽

Combined Therapy ◽

Dependent Manner ◽

Swiss Albino Mice ◽

Myristica Fragrans ◽

Albino Mice

AbstractThe current study aimed to evaluate the in vivo hypoglycemic potential of Myristica fragrans seed extract co-administered with glimepiride in Swiss albino mice. Computational tools were used to further verify the in vivo findings and to help compare this combination to the glimepiride-pioglitazone combination in terms of the binding affinity of the ligands to their respective target protein receptors and the relative stability of the drug-protein complexes. The effect of the combined therapy was observed both in alloxan- and glucose-induced hyperglycemic Swiss albino mice. The mean fasting blood glucose level of the test groups was measured and statistically evaluated using Student’s t test. The combined therapy significantly reduced the blood glucose level in a time-dependent manner compared to glimepiride alone. The binding affinity of glimepiride was found to be −7.6 kcal/mol with sulfonylurea receptor 1 in molecular docking. Conversely, macelignan-peroxisome proliferator-activated receptor (PPAR) α and macelignan-PPAR γ complexes were stabilized with −9.2 and −8.3 kcal/mol, respectively. Molecular dynamic simulation revealed that macelignan-PPAR α and γ complexes were more stable than pioglitazone complexes. The combination shows promise in animal and computer models and requires further trials to provide evidence of its activity in humans.

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High-Dose Calcitriol Modulates the Expression and Activity of Tissue Factor and Thrombomodulin in Tumor Cells.

Blood ◽

10.1182/blood.v110.11.921.921 ◽

2007 ◽

Vol 110 (11) ◽

pp. 921-921

Author(s):

Enriqueta Coll-Sangrona ◽

Ali Amirkhosravi ◽

Alshad S. Lalani ◽

Liza Robles ◽

Hina Desai ◽

...

Keyword(s):

Prostate Cancer ◽

Endothelial Cells ◽

Tumor Cells ◽

High Dose ◽

Dependent Manner ◽

High Concentrations ◽

Dose Dependent ◽

A549 Lung

Abstract Calcitriol, the hormonally-active metabolite of Vitamin D3, plays critical roles in calcium homeostasis, cell growth and differentiation, and immunoregulation. The anti-tumor activities of high-dose calcitriol have been demonstrated in a variety of preclinical models of solid tumors, leukemias and lymphomas. Recently, a new dose-intense formulation of calcitriol, termed DN-101 (Asentar™), was developed specifically for cancer therapy which allows for supraphysiological concentrations of calcitriol to be safely delivered in vivo to patients with cancer. In a recent Phase 2 clinical trial, DN-101 significantly increased overall survival and also reduced the incidence of thromboembolic events in men with androgen-independent prostate cancer receiving docetaxel-based chemotherapy. Based on previous observations we hypothesized that calcitriol’s anti-thrombotic effects in vivo may be due to the downregulation of Tissue Factor (TF) antigen and activity and/or upregulation of Thrombomodulin (TM). To test this hypothesis, we incubated A549 lung carcinoma, A375-C15 metastatic melanoma, THP-1 monocytic leukemia, and Eahy926 endothelial cells with increasing concentrations of calcitriol for 24 hrs. For TF induction, tumor cells were stimulated with TNFα for 5 hrs and activity was measured by a clotting assay and a thrombin generation assay (TGA). TM activity was measured by a chromogenic assay. TF and TM surface antigen were assessed by flow cytometry. Calcitriol prevented the induction of TF in TNFα-stimulated THP-1 cells in a dose-dependent manner (from 33% at 1 nM to 94% at 100 nM) as evidenced by a prolongation of plasma clotting time, a decrease in endogenous thrombin potential (ETP), and a reduction of surface TF antigen. In addition, the activity and surface expression of TM on THP-1 cells was increased significantly (40% and 3-fold respectively, P < 0.01) following 100 nM calcitriol treatment. Similarly, in TNFα-stimulated melanoma cells, calcitriol prevented the induction of TF activity (from 26% at 1 nM to 60% at 1 μM) and expression in a dose-dependent manner. High-dose calcitriol treatment also increased melanoma cell TM activity between 8% and 62%. In contrast, constitutively expressed TF activity and antigen were less affected by calcitriol in A549 lung carcinoma cells (12 to 28% reduction at concentrations between 1–100 nM) whilst TM activity and antigen were unaffected. In comparison to the tumor cells, calcitriol had no significant effect on TM or TF activity or antigen in TNFα-stimulated EAhy926 endothelial cells. In conclusion, we have demonstrated that high concentrations of calcitriol inhibit the induction of surface TF expression and upregulates TM in multiple tumor cell lines in vitro. The degree of the inhibition is proportional to the extent of TF induction by TNF-α. These in vitro results provide further support for the anticoagulant properties associated with high concentrations of calcitriol and may provide a rationale for understanding the lower incidence of thromboembolic complications observed in patients with metastatic prostate cancer treated with DN-101.

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Teratogenic effects of imidacloprid in rats: mechanistic role of oxidative stress

International Journal of Pharmacology and Toxicology ◽

10.14419/ijpt.v7i2.29828 ◽

2019 ◽

Vol 7 (2) ◽

pp. 35

Author(s):

Nermeen Borai El-Borai ◽

Seham Said Hadad ◽

Hanem Kamal Khalifa

Keyword(s):

Oxidative Stress ◽

High Dose ◽

Dependent Manner ◽

Teratogenic Effects ◽

Pregnant Rats ◽

Skeletal Malformations ◽

Fetal Malformations ◽

High Doses ◽

Dose Dependent

Extensive use of imidacloprid (IMI) insecticide in the agro-vet practices leads to continuous animal and human exposure. Exposure of pregnant dams to such insecticides results in fetal malformations. In the light of this, the present study was designed to investigate the teratogenic effects of two different doses of IMI and the possible mechanistic role of oxidative stress. Fifteen pregnant females were randomly divided into three equal groups and orally treated daily during organogenesis period (6-15th GD), control (distilled water), LD-IMI (45 mg/kg) and HD-IMI (90 mg/kg). All pregnant dams were exposed to caesarean section on GD 20. Exposure to IMI induced significant increase in the percentage of resorptions at high-dose with significant reduction of fetal and placental weights in a dose-dependent manner. External fetal morphological abnormalities were recorded only at high-dose while several visceral abnormalities were observed in fetuses at low- and high-doses. Significant increases in the percentages of fetal skeletal malformations were recorded only in the high-dose group. Significant changes in MDA, GSH levels and CAT activity with insignificant change in the level of H2O2 were recorded only in placentae of LD-IMI group. However, all these parameters recorded significant changes in serum of dams, placentae and liver of fetuses at high-dose. In conclusion, exposure of pregnant rats to IMI, particularly at higher-dose, during the period of organogenesis induced fetal teratogenic effects that may be related to its maternal and fetal oxidative damaging impacts.

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SODIUM FLUORIDE-INDUCED OXIDATIVE STRESS AND HISTOLOGICAL CHANGES IN LIVER OF SWISS ALBINO MICE AND AMELIORATION BY OCIMUM SANCTUM LINN.

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i9.26840 ◽

2018 ◽

Vol 11 (9) ◽

pp. 195 ◽

Cited By ~ 1

Author(s):

Bhagwendra Prakash ◽

Suresh Kumar Sabal ◽

Rajbala Verma ◽

John Pj ◽

Inderpal Soni

Keyword(s):

Oxidative Stress ◽

Drinking Water ◽

Body Weight ◽

Leaf Extract ◽

Mononuclear Cells ◽

Tap Water ◽

Ocimum Sanctum ◽

High Dose ◽

Swiss Albino Mice ◽

Albino Mice

Objective: The present study was designed to evaluate hepatotoxicity induced by sodium fluoride (NaF) in Swiss albino mice and amelioration by Ocimum sanctum Linn.Methods: Mice were divided into six groups, Group I received tap water, Group II received low dose of NaF (8 mg/L), Group III high dose of NaF (80 mg/L) in drinking water, Group IV tap water along with 250 mg/kg body weight/day leaf extract of O. sanctum Linn., Group V 8 mg/L NaF in drinking water and 250 mg/kg body weight leaf extract of O. sanctum Linn., and Group VI 80 mg/L NaF in drinking water along with leaf extract of O. sanctum Linn. 250 mg/kg body weight/day for 90 days. On the 91st day, the animals were autopsied and liver tissue samples were taken to assess histopathological changes and oxidative stress by estimating glutathione peroxidase, superoxide dismutase, and catalase.Results: A highly significant decrease in the activity of antioxidant enzymes occurred with the high dose (Group III). Hepatic histopathological architecture exhibited deformities, namely, ballooning, hypertrophy, hepatocellular necrosis, infiltration of mononuclear cells, deformed central vein, sinusoidal dilation, and binucleated cells. Low-dose group (Group II) showed a significant decrease in antioxidant enzyme levels as compared to control group, and histological sections of liver showed dilated sinusoids, infiltration of mononuclear cells, ballooning, and hypertrophy of hepatocytes. Groups IV and V showed no pathological features. Group VI showed less damage to the liver as compared to Group III.Conclusion: The results revealed that the administration of leaf extract of O. sanctum Linn. elicited protection against NaF-induced hepatotoxicity and oxidative stress. It may, therefore, be inferred that fluoride caused hepatotoxicity in Swiss albino mice at the tested dose levels can be ameliorated by O. sanctum Linn.

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Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells

Cancers ◽

10.3390/cancers11050681 ◽

2019 ◽

Vol 11 (5) ◽

pp. 681 ◽

Cited By ~ 9

Author(s):

Renuka V. Iyer ◽

Orla Maguire ◽

Minhyung Kim ◽

Leslie I. Curtin ◽

Sandra Sexton ◽

...

Keyword(s):

T Cells ◽

Low Dose ◽

Growth Delay ◽

High Dose ◽

Dependent Manner ◽

Sorafenib Treatment ◽

Baseline Activity ◽

Dose Dependent

The multikinase inhibitor sorafenib is the only standard first-line therapy for hepatocellular carcinoma (HCC). Here, we report the dose-dependent effects of sorafenib on the immune response, which is related to nuclear factor of activated T cells 1 (NFAT1) activity. In vitro and in vivo experiments were performed with low and high doses of sorafenib using human T cells and spontaneous developed woodchuck HCC models. In vitro studies demonstrated that following exposure to a high dose of sorafenib the baseline activity of NFAT1 in T cells was significantly increased. In a parallel event, high dose sorafenib resulted in a significant decrease in T cell proliferation and increased the proportion of PD-1 expressing CD8+ T cells with NFAT1 activation. In the in vivo model, smaller tumors were detected in the low-dose sorafenib treated group compared to the placebo and high-dose treated groups. The low-dose sorafenib group showed a significant tumor growth delay with significantly more CD3+ cells in tumor. This study demonstrates that sorafenib has immunomodulatory effects in a dose- and time-dependent manner. Higher dose of sorafenib treatment was associated with immunosuppressive action. This observed effect of sorafenib should be taken into consideration in the selection of optimum starting dose for future trials.

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Ochratoxin A Induces Oxidative Stress in HepG2 Cells by Impairing the Gene Expression of Antioxidant Enzymes

Toxins ◽

10.3390/toxins13040271 ◽

2021 ◽

Vol 13 (4) ◽

pp. 271

Author(s):

Enrique García-Pérez ◽

Dojin Ryu ◽

Chan Lee ◽

Hyun Jung Lee

Keyword(s):

Oxidative Stress ◽

Ochratoxin A ◽

Hepg2 Cells ◽

Mrna Level ◽

Dependent Manner ◽

In Vivo Models ◽

Dose Dependent ◽

And Oxidative Stress

Ochratoxin A (OTA) is a mycotoxin frequently found in raw and processed foods. While it is considered a possible human carcinogen, the mechanism of action remains unclear. OTA has been shown to be hepatotoxic in both in vitro and in vivo models and oxidative stress may be one of the factors contributing to its toxicity. Hence, the effect of OTA on human hepatocellular carcinoma, HepG2 cells, was investigated on oxidative stress parameters. The cytotoxicity of OTA on HepG2 was time- and dose-dependent within a range between 0.1 and 10 µM; while 100 μM of OTA increased the intracellular reactive oxygen species (ROS) in a time-dependent manner. Additionally, the levels of glutathione (GSH) were increased by 9.7% and 11.3% at 10 and 100 nM of OTA, respectively; while OTA at 100 μM depleted GSH by 40.5% after 24 h exposure compared with the control. Finally, the mRNA level of catalase (CAT) was downregulated by 2.33-, 1.92-, and 1.82-fold after cells were treated with 1, 10, and 10 μM OTA for 24 h, respectively; which was linked to a decrease in CAT enzymatic activity. These results suggest that oxidative stress is involved in OTA-mediated toxicity in HepG2 cells.

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Anticancer Potential of Aqueous Ethanol Seed Extract ofZiziphus mauritianaagainst Cancer Cell Lines and Ehrlich Ascites Carcinoma

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2011/765029 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 17

Author(s):

Tulika Mishra ◽

Madhu Khullar ◽

Aruna Bhatia

Keyword(s):

Cell Lines ◽

Ehrlich Ascites Carcinoma ◽

Seed Extract ◽

Ziziphus Mauritiana ◽

Dependent Manner ◽

Swiss Albino Mice ◽

Ehrlich Ascites ◽

Albino Mice

Ziziphus mauritiana(Lamk.) is a fruit tree that has folkloric implications against many ailments and diseases. In the present study, anticancer potential of seed extract ofZiziphus mauritiana in vitroagainst different cell lines (HL-60, Molt-4, HeLa, and normal cell line HGF) by MTT assay as well asin vivoagainst Ehrich ascites carcinoma bearing Swiss albino mice was investigated. The extract was found to markedly inhibit the proliferation of HL-60 cells. Annexin and PI binding of treated HL-60 cells indicated apoptosis induction by extract in a dose-dependent manner. The cell cycle analysis revealed a prominent increase in sub Go population at concentration of 20 μg/ml and above. Agarose gel electrophoresis confirmed DNA fragmentation in HL-60 cells after 3 h incubation with extract. The extract also exhibited potent anticancer potentialin vivo. Treatment of Ehrlich ascites carcinoma bearing Swiss albino mice with varied doses (100–800 mg/kg b.wt.) of plant extract significantly reduced tumor volume and viable tumor cell count and improved haemoglobin content, RBC count, mean survival time, tumor inhibition, and percentage life span. The enhanced antioxidant status in extract-treated animals was evident from decline in levels of lipid peroxidation and increased levels of glutathione, catalase, and superoxide dismutase.

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